Landino L M, Crews B C, Timmons M D, Morrow J D, Marnett L J
Department of Biochemistry, A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15069-74. doi: 10.1073/pnas.93.26.15069.
Peroxynitrite activates the cyclooxygenase activities of constitutive and inducible prostaglandin endoperoxide synthases by serving as a substrate for the enzymes' peroxidase activities. Activation of purified enzyme is induced by direct addition of peroxynitrite or by in situ generation of peroxynitrite from NO coupling to superoxide anion. Cu,Zn-superoxide dismutase completely inhibits cyclooxygenase activation in systems where peroxynitrite is generated in situ from superoxide. In the murine macrophage cell line RAW264.7, the lipophilic superoxide dismutase-mimetic agents, Cu(II) (3,5-diisopropylsalicylic acid)2, and Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin dose-dependently decrease the synthesis of prostaglandins without affecting the levels of NO synthase or prostaglandin endoperoxide synthase or by inhibiting the release of arachidonic acid. These findings support the hypothesis that peroxynitrite is an important modulator of cyclooxygenase activity in inflammatory cells and establish that superoxide anion serves as a biochemical link between NO and prostaglandin biosynthesis.
过氧亚硝酸盐通过作为组成型和诱导型前列腺素内过氧化物合酶的过氧化物酶活性的底物，激活这些酶的环氧化酶活性。纯化酶的激活可通过直接添加过氧亚硝酸盐或通过一氧化氮与超氧阴离子偶联原位生成过氧亚硝酸盐来诱导。在超氧原位生成过氧亚硝酸盐的系统中，铜锌超氧化物歧化酶完全抑制环氧化酶的激活。在小鼠巨噬细胞系RAW264.7中，亲脂性超氧化物歧化酶模拟剂Cu(II)(3,5-二异丙基水杨酸)2和Mn(III)四(1-甲基-4-吡啶基)卟啉剂量依赖性地降低前列腺素的合成，而不影响一氧化氮合酶或前列腺素内过氧化物合酶的水平，也不通过抑制花生四烯酸的释放来降低其合成。这些发现支持了过氧亚硝酸盐是炎症细胞中环氧化酶活性的重要调节剂这一假说，并证实超氧阴离子是一氧化氮与前列腺素生物合成之间的生化联系。
